The objective of this renewal application is to define the biological significance of atrial natriuretic factor (ANF) in the regulation of sodium homeostasis during the evolution of congestive heart failure (CHF) from initial compensated to overt decompensated ventricular failure. The specific locus is to elucidate the interactions between ANF and the renin-angiotensin system (RAS) in CHF. The conceptual hypothesis is that neurohumoral activation participates in biological regulation independently of altered ventricular function in CHF. Our working hypothesis is: Increased circulating ANF which occurs with the onset of chronic ventricular dysfunction serves to maintain a chronic phase of sodium balance and inhibit activation of the circulating RAS despite ventricular dysfunction. This increase in circulating ANF is secondary to enhanced cardiac synthesis and release which occurs in response to mechanogenic stimuli. this plasma increase is also secondary to enhanced pulmonary synthesis which is not present in the absence of CHF. An intact clearance receptor mechanism for ANF in the control of plasma concentrations prevent full increases in circulating ANF in CHF which limits its full biological actions. With activation of the RAS with advanced ventricular dysfunction, angiotensin II (Ang II) serves as a humoral stimulus for cardiac ANF synthesis but also mediates a renal hyporesponsiveness to ANF characterized by an attenuated renal generation of cGMP. Finally, the chronic use of diuretic therapy and AII receptor antagonism via modulation of the RAS attenuates or enhances respectively the renal biological responsiveness to ANF during evolving CHF. The Specific Aims of the current proposal are as follows: Aim I: To determine if ANF serves to maintain sodium balance and prevent activation of the circulating RAS in the compensated phase of evolving CHF. Aim II: To determine if the ANF clearance receptor mechanism in the control of total and regional ANF clearance limits the full plasma elevation and biological actions of circulation ANF in evolving CHF. Aim III: to determine in Ang II functions to increase cardiac synthesis of ANF in evolving CHF and, if the increase in circulating ANF is associated with enhanced pulmonary synthesis. Aim IV: To determine the basis for the attenuated increase in renal cGMP generation to ANF in overt CHF and the role of Ang II in this attenuated response. Aim V: To determine the contrasting actions of chronic diuretic therapy and AII receptor antagonism upon the RAS and renal biological responsiveness to ANF in evolving CHF.